Chen Yan, Li Xiaosong, Tian Lina, Lui Vincent C H, Dallman Margaret J, Lamb Jonathan R, Tam Paul K H
Division of Paediatric Surgery, Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, PR China.
Transplantation. 2007 May 27;83(10):1351-7. doi: 10.1097/01.tp.0000262568.73590.81.
Although acute graft rejection can be successfully controlled by immunosuppressive agents, chronic rejection (CR), which is characterized by arteriosclerosis in the donor organ vessels, is a major hurdle to long-term allograft survival. Sonic hedgehog (Shh), a morphogen critical in embryogenesis, also promotes peripheral immunity, which prompted us to investigate if inhibition of Shh signaling could reduce CR and thereby enhance allograft survival.
In a rat orthotopic small bowel transplantation model, FK506 prevented acute rejection; however, recipients eventually lost their grafts by CR. Anti-Shh antibody or isotype control were administered to animals at day 30 postoperatively. Graft survival, tissue fibrosis, vascular occlusion, and expression of vascular endothelial growth factor (VEGF) were investigated.
Immunostaining revealed that Shh and the Hedgehog receptor Patched 1 (Ptc1) are strongly expressed in CR grafts and that Ptc1 expression partially overlapped with that of ED-1, a macrophage marker. In contrast, only minimal expression of Shh and Ptc1 was detected in syngeneic grafts. Grafts survival was significantly prolonged after anti-Shh antibody treatment compared with the immunoglobulin G control (116 vs. 77.5 days). Collagen deposition and vascular occlusion in the mesentery were markedly reduced in recipients of the anti-Shh antibody. Specific transcripts and protein expression for VEGF, which was present mainly in the blood vessels, were reduced.
In a rat small bowel transplantation model, anti-Shh antibody treatment reduced CR and prolonged graft survival. These beneficial effects of Shh treatment may occur partly by reducing VEGF expression in the blood vessels of the allografts.
尽管急性移植排斥反应可通过免疫抑制剂成功控制，但以供体器官血管动脉硬化为特征的慢性排斥反应（CR）是同种异体移植长期存活的主要障碍。声波刺猬因子（Shh）是胚胎发育过程中的一种关键形态发生素，也可促进外周免疫，这促使我们研究抑制Shh信号是否能减少CR，从而提高同种异体移植的存活率。
在大鼠原位小肠移植模型中，FK506可预防急性排斥反应；然而，受体最终因CR失去移植物。术后第30天给动物注射抗Shh抗体或同型对照。研究移植物存活、组织纤维化、血管闭塞及血管内皮生长因子（VEGF）的表达情况。
免疫染色显示，Shh和刺猬因子受体Patched 1（Ptc1）在CR移植物中强烈表达，且Ptc1表达与巨噬细胞标志物ED-1部分重叠。相比之下，在同基因移植物中仅检测到Shh和Ptc1的微量表达。与免疫球蛋白G对照相比，抗Shh抗体治疗后移植物存活时间显著延长（116天对77.5天）。抗Shh抗体受体的肠系膜中胶原沉积和血管闭塞明显减少。主要存在于血管中的VEGF的特异性转录本和蛋白表达降低。
在大鼠小肠移植模型中，抗Shh抗体治疗可减少CR并延长移植物存活时间。Shh治疗的这些有益作用可能部分是通过降低同种异体移植物血管中VEGF的表达而实现的。
